Exposure to environmental chemical mixtures may pose hazards to human health. Polychlorinated biphenyls (PCBs) are common environmental contaminants that can act as promoters of carcinogenesis. Of two classes of important PCBs, the co-planar PCBs act through the Ah receptor and non-planar PCBs through a phenobarbital (PB)-like response. Synergistic hepatic tumor promotion occurs between the co-planar 3,3',4,4',5- pentachlorobiphenyl (PCB 126) and the non-planar 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). It is hypothesized that lack of response to transforming growth factor beta (TGF beta) inhibition of cell proliferation may be a common mechanism of promotion, contributing to the synergism. The long-term objectives of this project are: 1) to evaluate and qualify the synergistic hepatic tumor promotion activity of PCBs 126 and 153 alone and in combination and 2)to explore the role of TGF beta signaling as a possible mechanism for this synergistic activity. Liver tumor promotion will be evaluated via an 8 week initiation/promotion bioassay utilizing placental glutathione-S- transferase positive preneoplastic foci as an endpoint. Since TGF beta inhibits hepatocellular proliferation and stimulates apoptosis, both processes will be studied to determine if changes in proliferation and/or apoptosis correlate with promoting activity. Ah receptor agonist activity has been linked to abnormal TGF beta receptor formation and PB causes downregulation of TGF beta receptors. TGF beta receptor expression will be correlated with promotion, cell proliferation, and apoptosis, by performing quantitative assays for TGF beta levels, TGF beta receptor binding, and abnormal TGF beta receptor formation. The Principle Investigator on this project is Charles E. Dean Jr., DVM. Dr. Dean's goals are to prepare for a research career combining his training in toxicologic pathology and carcinogenesis. Dr. Dean will have completed his residency training in anatomic pathology and will spend full-time on this research at the Center for Environmental Toxicology and Technology at Colorado State University. He will be mentored by a faculty committee with research expertise in toxicology, pathology, molecular biology, and carcinogenesis.